Response to Treatment with TNF\u03b1 Inhibitors in Rheumatoid Arthritis Is Associated with High Levels of GM-CSF and GM-CSF+ T Lymphocytes

Jonas Bystrom,Rizgar A Mageed,Mohammed M Al-Bogami,Pamela Mangat,Ali S Jawad,Felix I Clanchy,Richard O Williams,Taher E Taher,Hawzheen A Muhammad,Saba Alzabin

doi:10.1007/s12016-017-8610-y

Abstract

Biologic TNFα inhibitors are a mainstay treatment option for patients with rheumatoid arthritis (RA) refractory to other treatment options. However, many patients either do not respond or relapse after initially responding to these agents. This study was carried out to identify biomarkers that can distinguish responder from non-responder patients before the initiation of treatment. The level of cytokines in plasma and those produced by ex vivo T cells, B cells and monocytes in 97 RA patients treated with biologic TNFα inhibitors was measured before treatment and after 1 and 3 months of treatment by multiplex analyses. The frequency of T cell subsets and intracellular cytokines were determined by flow cytometry. The results reveal that pre-treatment, T cells from patients who went on to respond to treatment with biologic anti-TNFα agents produced significantly more GM-CSF than non-responder patients. Furthermore, immune cells from responder patients produced higher levels of IL-1β, TNFα and IL-6. Cytokine profiling in the blood of patients confirmed the association between high levels of GM-CSF and responsiveness to biologic anti-TNFα agents. Thus, high blood levels of GM-CSF pre-treatment had a positive predictive value of 87.5% (61.6 to 98.5% at 95% CI) in treated RA patients. The study also shows that cells from most anti-TNFα responder patients in the current cohort produced higher levels of GM-CSF and TNFα pre-treatment than non-responder patients. Findings from the current study and our previous observations that non-responsiveness to anti-TNFα is associated with high IL-17 levels suggest that the disease in responder and non-responder RA patients is likely to be driven/sustained by different inflammatory pathways. The use of biomarker signatures of distinct pro-inflammatory pathways could lead to evidence-based prescription of the most appropriate biological therapies for different RA patients.

Highlights

Rheumatoid arthritis (RA) is a debilitating disease characterised by autoimmunity and the production of high levels of pro-inflammatory cytokines resulting in joint inflammation, the production of matrix-degrading enzymes and cartilage and bone destruction [1]
Ninety-seven RA patients prescribed anti-TNFα were recruited to the study (Table 2) and their clinical samples used in multiple experiments described in this report
No notable or consistent differences in cytokine production by enriched cells were seen between patients receiving different anti-TNFα agents

Summary

Introduction

Rheumatoid arthritis (RA) is a debilitating disease characterised by autoimmunity and the production of high levels of pro-inflammatory cytokines resulting in joint inflammation, the production of matrix-degrading enzymes and cartilage and bone destruction [1]. In this regard, a number of laboratories including ours have revealed that T cells from non-responder RA patients produce high levels of IL-17 and have a high frequency of circulating Th17 cells [11, 12]. The molecular basis and the physiological and therapeutic implications remain to be determined, these findings indicate that TNFα/TNFα blockade have significant impacts on the function and frequency of T cell subsets [13]. This suggestion is consistent with the association between T cell responses and signalling generated by TNFα through its two receptors in T cells [reviewed in [14]]

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Discussion

Conclusion